Long Acting Somatostatin Analogues

Octreotide and lanreotide are synthetic analogues of somato-statin that, because they are much more resistant to degradation than native somatostatin, have a much longer duration of action than native somatostatin and therefore can be used by intermittent subcutaneous injection. Like native somatostatin, these synthetic analogues suppress most intestinal secretions (gastric, pancreatic, biliary, intestinal), inhibit release of most GI hormones and neurotransmitters, and can inhibit GI motility. At present, only octreotide is available in the united States. Octreotide is the drug of choice for most large-volume, severe diarrheas. Numerous studies have demonstrated its effectiveness in VIPomas and diarrhea caused by carcinoid syndrome. These somatostatin analogues inhibit both the ectopic release of hormones and neuro-transmitters by these tumors and secretion from the large and small intestine stimulated by a number of agents (prostaglandin E1, serotonin, VIP); they also stimulate sodium chloride absorption in animal studies. Because of these actions, somatostatin analogues have been used to treat a number of secretory and nonsecretory diarrheal conditions, both hormonally and nonhormonally mediated. These include, in addition to VIPomas, carcinoid syndrome, medullary thyroid carcinomas, glucagonomas, diarrhea associated with acquired immune deficiency syndrome (AIDS), diarrhea owing to short bowel syndrome, diarrhea owing to dumping syndrome, and diarrhea owing to chemotherapy or bone marrow transplantation treatments. The specific use of octreotide in the various secretory hormonal diarrheas is discussed in the following section on these specific diseases. Octreotide use is also discussed in the chapters on AIDS (see Chapter 46, "Gastrointestinal and Nutritional Complications of HIV Infection"), short bowel syndrome (see Chapter 64, "Short Bowel Syndrome"), and stem cell transplantation (see Chapter 48,"Gastrointestinal and Hepatic Complications of Stem Cell Transplantation").

Octreotide

Treatment with somatostatin analogues is usually limited to severe diarrheas or those refractory to other treatments because of its cost and because parenteral administration is required (Farthing, 2002). The usual starting dose of octreotide, which is the only synthetic analogue available in the United States, is 50 to 100 |g 2 to 4 times a day administered subcutaneously. The dose and frequency can then be titrated to control the symptoms. Doses as high as 750 |g 3 times daily have been used. The half-life of octreotide is 100 minutes compared with 2 to 3 minutes for native somatostatin, and octreotide has been shown to be 70-fold more potent than native somatostatin at inhibiting growth hormone release and 80-fold more potent at inhibiting acid secretion. There have been a small number of reports of cases in which intermittent subcutaneous administration is not effective and a continuous infusion of octreotide is more effective. With continued treatment, octreotide may become less effective and increased dosage is frequently required (Fried, 1999).

Recently, a long-acting formulation of octreotide (octreotide-LAR [long-acting release]) has become available. This formulation is administered once per month intramuscularly. Three dosage forms are available, including 10,20, and 30 mg formulations. We usually begin with the 20 mg formulation in a patient in whom extended control of the SD will be required and who responds to the subcutaneous formulation. It is important to continue the subcutaneous formulation for at least 2 weeks after starting the octreotide-LAR because it takes that long to reach appropriate blood levels with the long-acting form. In patients with carcinoid syndrome or VIPomas, even after octreotide-LAR has been given for a number of months, it may have to be supplemented with subcutaneous octreotide periodically for acceptable symptom control (Szilagyi and Shrier, 2001).

The side effects of treatment with synthetic somatostatin analogues include cramping or nausea, which usually resolve with continued treatment, and pain at the subcutaneous injection site, which may be reduced by slow injection and warming the vial. Worsening of glucose tolerance develops in some patients, and it is advisable to obtain a serum glucose determination when beginning the medication. A small percentage of patients may develop fat malabsorption. Long term, the principal side effect is the development of biliary sludge or gallstones, thought to be due to the ability of somatostatin to inhibit gallbladder emptying. In various studies with long-term treatment, 10 to 50% of patients have developed biliary sludge or gallstones, but in only 1 to 10% is it symptomatic. With long-term treatment, an ultrasound examination of the gallbladder before the treatment and every 6 to 12 months should be considered (Redfern and Fortuner, 1995).

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